Project Summary: This project aims to establish near-infrared spectroscopy (NIRS), which is a non-invasive optical technique sensitive to cerebral hemodynamic changes, as a tool to monitor intracranial pressure (ICP) non-invasively. The healthy brain maintains a relatively constant blood flow even during episodes of stress and changes in cerebral perfusion pressure (CPP), which is defined as the difference between mean arterial pressure (MAP) and intracranial pressure (ICP). The mechanism preserving blood flow is called cerebral autoregulation (CA), which is known to be impaired in a variety of diseases. Cerebral autoregulation can be evaluated by means of pressure reactivity, by correlating changes in MAP to ICP. In the healthy brain, changes in MAP are counterbalanced by changes in ICP and autoregulation is thought to be intact. When autoregulation is impaired, such as in traumatic brain injured patients, MAP changes are directly translated to and correlated with ICP changes. Using this metric of correlation to guide CPP management in traumatic brain injury patient has shown to improve patient outcome, while managing MAP alone, without considering correlation to ICP, does not, thus demonstrating the importance of ICP measurements. However, this requires ICP to be measured by placing an invasive pressure sensor in the brain. While CPP management is hypothesized to benefit patients with impaired autoregulation, placing an ICP sensor is not always an option and recommended in a variety of diseases, including stroke, sepsis, and Parkinson?s. In addition, neuronal activity plays a role in cerebral autoregulation due to neuro-vascular coupling, but is generally not taken into account for CPP management. Neurovascular coupling is known to be disrupted in hypertension, Alzheimer disease, and ischemic stroke, which may be due to impaired autoregulation. However, the relationship between neurovascular coupling, CPP, and autoregulation has not been explored in detail. Therefore, this proposals is aiming at establishing NIRS as a non-invasive alternative to monitoring ICP for guiding clinical management of CPP. For this we will first perform experiments on non-human primates, where controlled changes in ICP and MAP will be induced while measuring hemodynamic changes with NIRS. Using a transfer function approach, we will establish the mathematical tools to translate changes in hemoglobin concentration into ICP traces. Furthermore, we will use electrode arrays (?Utah? array) combined with NIRS sensors during resting state and a functional activation, again in non-human primates. These experiments will allow us to quantify neuro-vascular coupling by means of the hemodynamic response function as a function of ICP and CPP. Combined, the results from these experiments will allow us to establish NIRS for ICP monitoring and will pave the way for management of CPP in patients where ICP measurements are not possible, ultimately not only providing tools for advanced monitoring of disease but improving treatment of disease and patient outcome.